Hypertension afflicts about 33% of the adult population and is antecedent to myocardial infarction, heart failure, stroke, and renal disease which contribute to 1 in 3 deaths. This problem is growing. The American Heart Association predicts that by 2030 hypertension prevalence will increase by 8%. Hypertension control was suggested as a public health initiative with one of the greatest impacts on mortality. Despite increased awareness and current therapies, hypertension control remains suboptimal in 50% of patients indicating the need for new paradigms in blood pressure control. Our group and others showed that venous tone and cardiopulmonary volume were increased in hypertensive animals and humans which contribute to hypertension initiation and maintenance. Yet, the venous compartment remains largely unexplored as a target to control blood pressure, in large part due to fragmented knowledge about mechanisms outside of the baroreceptors that control venous tone. Our ultimate goal is to advance the field by revealing novel mechanisms controlling venous tone and their dysregulation in disease (e.g. hypertension). This project tests the concepts that cardiac sympathetic afferent neural reflexes control venous function via the hypothalamic paraventricular nucleus (PVN) and that pathological over activity of this pathway leads to augmented venoconstriction that contributes to the initiation and maintenance of hypertension. Specific Aim I will define the extent to which cardiac sympathetic afferents control venous tone, cardiac filling, cardiac output and blood pressure. Our work identified the PVN as a brain site regulating venous tone. Specific Aim II will determine whether the PVN plays a critical role in cardiac sympathetic afferent control of venous tone. Dysregulation of afferent signaling pathways are often overlooked as triggers for cardiovascular disease. Specific aim III will test the hypothesis that over activity of the cardiac sympathetic afferent reflex contributes to enhanced venoconstriction and interruption of this mechanism attenuates hypertension. Collectively we expect this project to establish that the cardiac sympathetic afferent reflex is novel mechanism for controlling venous tone, cardiac filling and blood pressure. Dysregulation of this venous control mechanism contributes to venoconstriction in hypertension and that interruption of this mechanism reduces venous tone and high blood pressure. These studies will provide an important foundation for future work studying the cardiac sympathetic afferent reflex as a novel therapeutic target for conditions where venous return is abnormal.